Nano-suspensions are emerging as a preferential form of active pharmaceutical compounds which are BCS class II and class IV (aqueous insoluble) drug substances in the provision of oral and injectable medicaments comprising such compounds. Reviews highlighting the possibilities of this approach in the provision of medicaments include: Critical Reviews in articles by Bala, I. et al. in PLGA Nanoparticles in Drug Delivery: State of the Art, Therapeutic Drug Carrier Systems, 2004, Vol 21, issue 5; Rabinow, B. E. in Nanosuspensions in Drug Delivery, Nature Reviews, Drug Discovery, Vol 3 (2004) pp 785-796; Patravale, V. B. et al. in Nanosuspensions: a promising drug delivery strategy, Journal of Pharmacy and Pharmacology, (2004) 56: pp 827-840; and Koteshwara, K. B. et al. in Nanosuspensions: a Novel Drug Delivery Approach, Int. Journal. Of Res. In Ayurveda & Pharmacy, (2011), 2(1) pp 162-165. When utilized in medicaments for oral administration, nano-suspensions of class II and class IV drug substances can provide a dosage form which addresses the twin problems of low solubility and poor bioavailability by providing these compounds in a form in which the very small particle size presents an extremely large surface area of the compound to the biosystem to which it is administered, reducing bathers to dissolution and absorption. When utilized in medicaments for administration via injection, nano-suspensions can provide a dosage form which contains high drug loading and is readily dispersed within the system into which it is injected.
Typically, nano-suspensions of active pharmaceutical compounds are prepared by application of extremely high shear conditions to a mixture of the compound, an aqueous dispersion medium, and milling media (herein, “high-shear milling”). In most high-shear milling applications the milling media is a small polyester prill driven by the shear forces to which it is subjected, and acts like a microscopic ball mill, impacting the pharmaceutical compound present in the mixture (generally, the active pharmaceutical compound (APC) is present in the slurry initially as a powder, in the form of a macroscopic particulate, with D50 in excess of one micron). Typical equipment employed in preparing such nano-suspensions is a high-shear mixer in which a stainless steel impeller rotates at multiple thousand RPM in a chamber holding a mixture of the active pharmaceutical compound, aqueous dispersion medium, and milling media. An example of commercially available equipment utilized in this process is the Elan Nanomill®.
There have been reports of difficulties presented in the provision of nano-suspensions using a high-shear mixing process, for example, shedding of metal particles as a result of the high-shear stresses imposed on the equipment used in preparing the nano-suspension, heating of the admixture from which the nano-suspension is prepared, resulting in degradation of drug product, limitations on drug loading, and long periods of mixing required to prepare nano-suspensions mitigate against using such a process for providing commercial quantities of a nano-suspension of an APC for use in commercial preparation of medicaments. In addition to these drawbacks, scaling high-shear milling equipment and processes from “bench-scale” preparation of a nano-suspension to a commercial scale requires extensive engineering and process development. The need for a mixing and recirculating chamber imposed by the high-shear process requirements presents special difficulties in adopting such processes for aseptic manufacturing. The ability to compare various formulations in the development of a nano-suspension as an active pharmaceutical ingredient for commercial scale production of medicaments also presents difficulties such as equipment-limited throughput of screening formulations and the difficulties in maintaining consistent conditions across multiple runs using different formulations.
In view of the foregoing, there is a need for improving the process by which nano-suspensions are prepared.
Acoustic mixers, for example, the Resodyn™ acoustic mixer, are commercially available. This technology has been described, for example, in U.S. Pat. No. 7,188,993 to Howe et al., and employs linear displacement to introduce a standing linear acoustic wave into a medium, for example, gas, liquid or solid, residing within a container affixed to the device. Preparation of admixtures comprising energetic or shock-sensitive materials has been described using acoustic mixing, for example, in Published U.S. Patent Application 2010/0294113 (McPherson). Suspension of pre-formed nanoparticulate materials in an aqueous medium has also been described, for example, the dispersion of silver nanoparticles of 20 nm-30 nm in water using an acoustic mixer (Resodyn™ marketing literature)